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WO2006133198A2 - Medicaments anti-vhs - Google Patents

Medicaments anti-vhs Download PDF

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Publication number
WO2006133198A2
WO2006133198A2 PCT/US2006/021931 US2006021931W WO2006133198A2 WO 2006133198 A2 WO2006133198 A2 WO 2006133198A2 US 2006021931 W US2006021931 W US 2006021931W WO 2006133198 A2 WO2006133198 A2 WO 2006133198A2
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WO
WIPO (PCT)
Prior art keywords
herpes simplex
simplex virus
types
pharmaceutical composition
enantiomers
Prior art date
Application number
PCT/US2006/021931
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English (en)
Other versions
WO2006133198A3 (fr
Inventor
Jong Joseph Kim
Original Assignee
Vgx Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vgx Pharmaceuticals, Inc. filed Critical Vgx Pharmaceuticals, Inc.
Publication of WO2006133198A2 publication Critical patent/WO2006133198A2/fr
Publication of WO2006133198A3 publication Critical patent/WO2006133198A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Definitions

  • the present invention further relates to pharmaceutical composition
  • pharmaceutical composition comprising: a pharmaceutically acceptable carrier or diluent; and, a compound that inhibits HSV replication, the compound having a structure selected from the group consisting of mifepristone, Formula Dl, Formula D2, Formula D3, Formula D4, Formula D5, and pharmaceutically acceptable salts thereof.
  • the present invention further relates to methods of treating an individual who has been infected with HSV.
  • the method comprise the step of administering to the individual an amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and, a compound that inhibits HSV replication having a structure selected from the group consisting of mifepristone, Formula Dl, Formula D2, Formula D3, Formula D4, Formula D5, and pharmaceutically acceptable salts thereof effective to inhibit HSV replication in the individuals.
  • the present invention further relates to methods of preventing HSV infection in an individual at an elevated risk of becoming HSV infected.
  • the method comprise the step of administering to the individual a prophylactically effective amount of a pharmaceutical composition that comprises a pharmaceutically acceptable carrier or diluent, and, a compound that inhibits HSV replication having a structure selected from the group consisting of mifepristone, Formula Dl, Formula D2, Formula D3, Formula D4, Formula D5, and pharmaceutically acceptable salts thereof effective to inhibit HSV replication.
  • the present invention provides pharmaceutical compositions comprising a compound having a structure selected from the group consisting of mifepristone, Formulad Dl -D 18 and pharmaceutically acceptable salts thereof.
  • the present invention provides methods of treating individuals infected with HSV by administering to them a therapeutically effective amount of such compositions.
  • the present invention further provides methods of preventing HSV infection in individuals exposed to HSV 5 by administering to them a prophylactically effective amount of such compositions.
  • the present invention is useful to therapeutically treat an individual identified as infected with HSV in order to eliminate, reduce or stabilize viral titer.
  • the present invention is useful to prophylactically treat a high risk individual from becoming infected with HSV.
  • the compounds of the invention may act as steroid hormone receptor antagonists that interactively blocks Rip-l/mov34, alone or in association with one or more steroid receptors, or other components, or one or more steroid receptors alone, preventing or inhibiting formation and translocation of the Rip-1 and/or steroid receptor or other EIF component complex.
  • high risk individual is meant to refer to an individual who is suspected of having been exposed to the HSV virus. Such individuals include health care or other individuals who may have accidently exchanged blood with an HSV-infected individual, such as through an accidental needle stick, injuries that occur during emergency medical care, rescue or arrest and unprotected sexual contact. High risk individuals can be treated prophylactically before any detection of HSV infection can be made.
  • the term "therapeutically effective amount” is meant to refer to an amount of a compound which produces a medicinal effect observed as reduction or reverse in viral titer when a therapeutically effective amount of a compound is administered to an individual who is infected with HSV.
  • Therapeutically effective amounts are typically determined by the effect they have compared to the effect observed when a composition which includes no active ingredient is administered to a similarly situated individual.
  • prophylactically effective amount is meant to refer to an amount of a compound which produces a medicinal effect observed as the prevention of HSV infection in an individual when a prophylactically effective amount of a compound is administered to a high risk individual.
  • Prophylactically effective amounts are typically determined by the effect they have compared to the effect observed when a composition which includes no active ingredient is administered to a similarly situated individual.
  • the invention provides novel pharmaceutical compositions comprising antiviral compounds that are inhibitors of HSV replication.
  • the antiviral compounds included in the pharmaceutical compositions of the present invention have a formula selected from the group consisting of mifepristone and Formulas Dl -D 18 as set forth below, or a pharmaceutically acceptable salt thereof at doses effective in treating HSV.
  • the invention provides novel pharmaceutical compositions comprising antiviral compositions that inhibit HSV replication.
  • the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of mifepristone as set forth in the section below entitled Formulae.
  • the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 1 as set forth in the section below entitled Formulae.
  • the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 2 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 3 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 4 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 5 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 6 as set forth in the section below entitled Formulae.
  • the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 7 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 8 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 10 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 5 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 11 as set forth in the section below entitled Formulae.
  • the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 12 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 13 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 14 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 15 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 16 as set forth in the section below entitled Formulae.
  • the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 17 as set forth in the section below entitled Formulae. In some preferred embodiments, the HSV replication inhibitor in the pharmaceutical compositions of the present invention has a formula of Formula 18 as set forth in the section below entitled Formulae.
  • the method of the invention additionally includes the use of the HSV replication inhibitor compositions of the invention in combination with other methodologies to treat HSV infection.
  • the HSV replication inhibitor is administered in conjunction with other antiviral agents such as acyclovir, ganciclovir, foscarnet, lamivudine, ribavirin, interferon alpha-2a, interferon alpha-2b, peginterferon alfa-2a, and peginterferon alfa-2b.
  • compositions comprising HSV replication inhibitor compositions of the present invention may be administered by any means that enables the active agent to reach the agent's site of action in the body of the individual.
  • Pharmaceutical compositions of the present invention may be administered by conventional routes of pharmaceutical administration.
  • Pharmaceutical compositions may be administered parenterally, i.e. intravenous, subcutaneous, intramuscular, subdermally, transdermally.
  • the pharmaceutical compositions are administered orally.
  • Pharmaceutical compositions are administered to the individual for a length of time effective to eliminate, reduce or stabilize viral titer.
  • Pharmaceutical compositions are administered to the individual for a length of time during which monitoring for evidence of infection continues.
  • compositions of the present invention may be administered either as individual therapeutic agents or in combination with other therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • Dosage varies depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a daily dosage of active ingredient can be about 0.001 to 1 grams per kilogram of body weight, in some embodiments about 0.1 to 100 milligrams per kilogram of body weight.
  • ordinarily dosages are in the range of 0.5 to 50 milligrams per kilogram of body weight, and preferably 1 to 10 milligrams per kilogram per day.
  • the pharmaceutical compositions are given in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.
  • Dosage forms (composition) suitable for internal administration generally contain from about 1 milligram to about 500 milligrams of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95 by weight based on the total weight of the composition.
  • multiple administrations are performed.
  • compositions may be formulated by one having ordinary skill in the art with compositions selected depending upon the chosen mode of administration. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field, which is incorporated herein by reference.
  • the compound can be formulated as a solution, suspension, emulsion or lyophilized powder in association with a pharmaceutically acceptable parenteral vehicle.
  • a pharmaceutically acceptable parenteral vehicle examples include water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used.
  • the vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives).
  • the formulation is sterilized by commonly used techniques.
  • a parenteral composition suitable for administration by injection is prepared by dissolving 1.5% by weight of active ingredient in 0.9% sodium chloride solution.
  • the composition is administered to tissue of an individual by topically or by lavage.
  • the compounds may be formulated as a cream, ointment, salve, douche, suppository or solution for topical administration or irrigation.
  • the compounds may be formulated as a transdermal patch or subdermal implants. Formulations for such routes administration of pharmaceutical compositions are well known. Generally, additives for isotonicity can include sodium chloride, dextrose, mannitol, sorbitol and lactose.
  • isotonic solutions such as phosphate buffered saline are used.
  • Stabilizers include gelatin and albumin.
  • a vasoconstriction agent is added to the formulation.
  • the pharmaceutical preparations according to the present invention are preferably provided sterile and pyrogen free.
  • the pharmaceutical preparations according to the present invention which are to be used as injectables are provided sterile, pyrogen free and particulate free.
  • a pharmaceutically acceptable formulation will provide the active ingredient(s) in proper physical form together with such excipients, diluents, stabilizers, preservatives and other ingredients as are appropriate to the nature and composition of the dosage form and the properties of the drug ingredient(s) in the formulation environment and drug delivery system.
  • the invention relates to methods of treating patients suffering from HSV infection. In some embodiments, the invention relates to methods of preventing HSV infection in high risk individuals.
  • the patient is treated with other antiviral therapy in conjunction the administration of pharmaceutical compositions according to the invention.
  • the use of multiple therapeutic approaches provides the patient with a broader based intervention.
  • the individual in combination with administration of the composition that comprises the HSV replication inhibitor, is also administered another agent.
  • the individual in combination with administration of the composition, the individual additionally receives compositions that comprises acyclovir, valcyclovir, famciclovir, ganciclovir, foscarnet, lamivudine, ribavirin, interferon alpha-2a, interferon alpha-2b, peginterferon alfa-2a, and peginterferon alfa-2b.
  • the pharmaceutical compositions contain one or more of the compounds selected from the group consisting of mifepristone, Formulas Dl -D 18, and pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions contain one or more of the compounds selected from the group consisting of mifepristone, Formulas Dl- D 18, and pharmaceutically acceptable salts thereof and at least one additional antiviral selected from the group consisting of: acyclovir, valcyclovir, famciclovir, ganciclovir, foscarnet, lamivudine, ribavirin, interferon alpha-2a, interferon alpha-2b, peginterferon alfa-2a, and peginterferon alfa-2b, together with a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions according to the present invention may be administered as a single doses or in multiple doses.
  • the pharmaceutical compositions of the present invention may be administered either as individual therapeutic agents or in combination with other therapeutic agents.
  • the treatments of the present invention may be combined with conventional therapies, which may be administered sequentially or simultaneously.
  • the present invention relates to methods of preventing HSV infection in high risk individuals who, for example, are suspected of having been exposed to the virus.
  • the present invention is particularly useful to prevent recurrence of infection in patients who have been previously diagnosed as HSV positive but show no indication of infection.
  • the present invention is not limited to any particular theory or mechanism of action and while it is currently believed that the compounds identified herein operate through blocking the steroid hormone receptor complex that comprises Rip-l/mov34, such explanation of the mechanism of action is not intended to limit the invention.
  • the present invention is further illustrated by the following examples, which are not intended to be limiting in any way.
  • the unbound Mifepristone is metabolized by two-step demethylation or by hydroxylation, and the initial metabolic steps are catalysed by the cytochrome P450 (CYP) enzyme CYP3A4 (Reilly et al, 1999).
  • CYP cytochrome P450
  • CYP3A4 cytochrome P450 enzyme
  • Three metabolites of Mifepristone have been identified (Sarkar, 2002). This compound undergoes demethylation to produce mono-demethylated and di-demethylated derivatives as well as hydroxylation of the propynyl group to yield hydroxylated metabolite.
  • these metabolites are immunologically and biologically active and retain anti-progestational and anti-glucocorticoid properties.
  • the relative binding affinities of the metabolites to the human glucocorticoid receptor are 61, 48 and 45% for the monodemethylated, hydroxylated, and didemethylated metabolites, respectively; each was higher than that of dexamethasone or Cortisol (23%).
  • EIF3/ICP27 complex is important for viral protein translation of herpes simplex virus (HSV) families and other viruses.
  • GRII antagonist drugs including Mifepristone, can target and disrupt function/structure of mov34, a member of EIF3 complex.
  • HSV Herpes Simplex Virus
  • HSV gene expression is characterized by a temporal pattern of expression of three gene classes: immediate early (IE), early (E), and late (L) genes.
  • IE genes are transcribed in the absence of de novo viral protein synthesis, E genes are activated by IE gene products, and L genes are activated by viral DNA synthesis (reviewed in Roizman and Knipe, 2001).
  • the IE-infected cell protein 27 (ICP27) is essential for viral replication and expression of certain early and nearly all late viral genes (Rice et al., 1989, Sacks et al., 1985 and Uprichard and Knipe, 1996).
  • ICP27 is a multi-functional protein in that it increases late viral gene transcription (Jean et al., 2001), binds to RNA (Mears and Rice, 1996), associates with RNA pol II (Zhou and Knipe, 2002), and shuttles from the nucleus to the cytoplasm (Mears and Rice, 1998 and Soliman et al., 1997).
  • ICP27 has been shown to associate with cellular transcriptional proteins (Taylor and Knipe, 2004 and Zhou and Knipe, 2002), as well as viral transcriptional proteins ICP4 (Panagiotidis et al., 1997) and ICP8 (Taylor and Knipe, 2004 and Zhou and Knipe, 2002), and function in post- transcriptional processes, such as pre-mRNA splicing and niRNA export, through its interactions with cellular splicing and export factors involved in these pathways (Koffa et al., 2001).
  • ICP27 directly affects the expression and stability of specific viral and cellular transcripts in both transfected (Brown et al., 1995) and infected cells (Cheung et al., 2000, Ellison et al., 2000 and Pearson et al., 2004). Furthermore, ICP27 is thought to function, along with the virion host shut-off (vhs) protein, in shut-off of cellular protein synthesis (Sacks et al., 1985 and Song et al., 2001), and the involvement of ICP27 in inhibition of pre-mRNA splicing provides a mechanism for shut-off of cellular protein synthesis (Sandri-Goldin, 1998).
  • vhs virion host shut-off
  • EIF3 is important for viral protein translation
  • eIF4G The interaction of eIF4G and PABP is thought to facilitate the interaction between the 5' cap and 3' polyadenylated end of the mRNA, which enhances translation both in vitro and in vivo, and facilitates recruitment of the 4OS ribosomal subunit to the 5' end of the mRNA molecule [(reviewed in Prevot et al., 2003) and (Sonenberg and Dever, 2003)].
  • eIF3 is a multi-subunit component of the 4OS ribosome, and interaction of eIF4G with eIF3 leads to recruitment of mRNA to the 43 S complex (reviewed (Gallie, 2002).
  • both eIF3 and PABP could lead to the recruitment of these translation initiation factors to viral mRNA and stimulation of translation of these mRNAs.
  • both PABP and eIF3 p47 subunit have been shown to localize to both the cytoplasm and the nucleus (Afonina et al., 1998 and Shi et al., 2003). Therefore, ICP27 could recruit these proteins to nascent viral transcripts, which may facilitate viral mRNA export out of the nucleus, and increase the efficiency of translational initiation on these mRNAs.
  • PABP, eIF3, and eIF4G are known targets for modification by viruses. These cellular translation factors are altered by specific viral proteins, and as a result, host cell protein synthesis is shut down (reviewed in Bushell and Sarnow, 2002 and Daughenbaugh et al., 2003).
  • Translation initiation factor eIF4G acts as a scaffolding protein for the cap-binding complex (eIF4F), and interacts with multiple translation initiation proteins including PABP and eIF3 (reviewed in Kawaguchi and Bailey-Serres, 2002). Furthermore, each of these translation initiation factors have been shown to function in viral translation regulatory mechanisms, which require specific binding to viral proteins (reviewed in GaIHe 5 2002).
  • GRII antagonist drugs can disrupt function/structure of mov34, a member of EIF3 complex
  • hVIP/mov34 Vpr Interacting Protein
  • Glucocorticoids regulate diverse functions and are important to maintain central nervous system, cardiovascular, metabolic, and immune homeostasis. They also exert antiinflammatory and immunosuppressive effects, which have made them invaluable therapeutic agents in numerous diseases (Chrousos, 1995). The actions of these hormones are mediated by their specific intracellular receptors, such as the GR. Several host co- activators of the GR have been described that directly interact with GR and components of the transcription initiation complex to enhance the glucocorticoid signal to the transcription machinery (Shibata et al., 1997).
  • the GR is the prototypic member of the translocating class of steroid receptors that are ubiquitously expressed in almost all human tissues and organs. Unliganded GR is found in the cytoplasm and moves rapidly into the nucleus in response to hormone stimulation (Htun et al., 1996, McNally et al., 2000). GR interacts in the cytoplasm with a complex array of chaperone proteins, including HSP90 and HSP70, and ligand-dependent displacement of these proteins is thought to be intimately involved in the translocation process (Bamberger et al., 1996, Beato et al., 1996). Both GR and hVIP are known Vpr ligands.
  • Steroid hormone receptor antagonists such as mifepristone prevent the GR from moving into the nucleus in response to appropriate stimulation.
  • mifepristone blocks the Vpr-induced nuclear entry of hVIP.
  • HVIP had been reported as a potential Vpr ligand and demonstrated its role in cell cycle regulation as antisense of this gene induced cell cycle arrest at the G2/M phase (Mahalingam et al., 1998).
  • Glucocorticoids have been demonstrated to mimic the effects of Vpr in HIV infection; Glucocorticoid antagonist mifepristone has been shown to revert these effects of Vpr (Ayyavoo et al., 1997, Ayyavoo et al., 2002, Kino et al., 1999, Sherman et al., 2000). Moreover, mifepristone has been shown to block the nuclear translocation of hVIP induced by Vpr in cells by inhibiting GR as a complex with hVIP/mov34.
  • Transdermal drug delivery is an increasingly important method of drug administration.
  • Transdermal drug delivery devices typically involve a carrier (such as a liquid, gel, or solid matrix, or a pressure sensitive adhesive) into which the drug to be delivered is incorporated.
  • the drug-containing carrier is then placed on the skin and the drug, along with any adjuvants and excipients, is delivered to the skin.
  • the portions of the carrier that are not in contact with the skin are covered by a backing.
  • the backing serves to protect the carrier (and the components contained in the carrier, including the drug) from the environment and prevents loss of the ingredients of the drug delivery device to the environment.
  • Backing materials that have found use in transdermal drug delivery devices include metal foils, metalized plastic films, and single layered and multilayered polymeric films.
  • Transdermal drug delivery utilizes the skin for the delivery of the drug molecules from the surface of the skin, through its layers, to the circulatory system.
  • the transdermal drug delivery technology comprises of a controlling system that regulates the rate of drug delivery to the skin, and another that uses the skin to control the absorption rate.
  • Transdermal drug delivery occurs in two ways: passive and active transdermal delivery.
  • Passive systems allow the drug to diffuse through the skin into the bloodstream using a simple concentration gradient as a driving force.
  • Active delivery system requires a physical force to facilitate the movement of drug molecules across the skin.
  • the first transdermal patch was introduced in 1981. Subsequently, the applications of transdermal drug delivery have been expanded to include more products in multiple therapeutic areas. Numerous kinds of medications have been administered through the use of a patch, notably scopolamine for preventing motion sickness, nicotine derivatives intended to discourage an addicted smoker from continuing the smoking habit and estrogen hormones.
  • U.S. Patent No. 5,223,261 describes a loading and using a transdermal delivery system for delivering estradiol.
  • U.S. Patent No. 5,380,760 describes a transdermal delivery system for delivering prostaglandin.
  • U.S. Patent No. 5,702,720 describes a transdermal delivery system for delivering flurbiprofen.
  • U.S. Patent No. 6,132,760 describes a transdermal delivery system for delivering testosterone.
  • the amount of drug that constitutes a therapeutically effective amount varies according to the condition being treated, any drugs being coadministered with the drug, desired duration of treatment, the surface area and location of the skin over which the device is to be placed, and the selection of adjuvant and other components of the transdermal delivery device. Accordingly, it is not practical to enumerate particular preferred amounts but such can be readily determined by those skilled in the art with due consideration of these and other appropriate factors. Generally, however, the drug is present in the adhesive layer in an amount of about 2 to about 9 percent, preferably about 2.5 to about 6.5 percent, by weight based on the total weight of the adhesive layer.
  • a device of the invention preferably contains a therapeutically effective amount of the drug dissolved in the adhesive layer.
  • the adhesive layer of the device of the invention also comprises one or more polymers, typically one or more copolymers.
  • the polymer(s) utilized in the practice of the invention should be substantially chemically inert to the drug, and is preferably a pressure sensitive skin adhesive.
  • suitable types of adhesives include acrylates, natural and synthetic rubbers, polysiloxanes, polyurethanes, and other pressure sensitive skin adhesives known in the art, either alone or in combination.
  • the adhesive is an acrylate copolymer.
  • the present invention provides transdermal drug delivery devices containing mifepristone, Compositions D1-D5 or other GRII antagonists (Drugs).
  • the drug is present in the adhesive layer in a therapeutically effective amount, i.e., an amount effective to allow the device to deliver sufficient amount of the drug to achieve a desired therapeutic result in the treatment of a condition.
  • a delivery of mifepristone via a transdermal patch would reduce the number of drugs a patient must take orally and improve compliance.
  • the transdermal drug delivery would be most appropriate in cases where low systemic and steady state drug concentration is desirable. This delivery method could enhance patient compliance and could reduce the effects of potential drug toxicities.
  • Transdermal drug delivery is not subjected to first-pass effect and does not cause frequent drag concentration alterations as compared to the drugs delivered through the oral route. This reduces the required dose in comparison to the oral drug delivery.
  • Medications delivered via skin patches avoid liver metabolism and hence allow for lower doses of medication. It also avoids potential toxicity of the drag to the liver.
  • the transdermal drag delivery also offers the flexibility of terminating the drag administration by simply removing the patch from the skin. This delivery system releases a controlled amount of a drag over a long period of time.
  • Transdermal patch systems exhibit slow controlled drag release and absorption and the plasma drag concentration does not vary significantly over time. This delivery method would enhance patient compliance and thereby a reduction of drag resistant viruses as well as reduce the effects of potential drag toxicities.
  • a principal advantage of employing sustained-release compositions is that many therapeutic agents would otherwise be rapidly metabolized or cleared from the patient's system necessitating frequent administration of the drag to maintain a therapeutically effective concentration.
  • “Matrix” type devices typically consist of an active compound dispersed in a matrix of carrier material which may be either porous or non- porous, solid or semi-solid, and permeable or impermeable to the active compound. These devices are rather easily prepared; however, they are not suitable for administering some pharmacologically active compounds. In addition, the rate of release of the active compound decreases with time.
  • "Reservoir” type devices consist of a central reservoir of active compound surrounded by a rate controlling membrane (rcm). The rcm is generally a porous or a non-porous material which is non-biodegradable.
  • the rate controlling membrane In the case of the transdermal devices of this type, to maintain an effective concentration of active compound, the rate controlling membrane must have a large surface area. Thus, a common disadvantage of these devices is that their large size makes administration quite inconvenient.
  • Other sustained release devices are hybrid-type devices which contain a matrix core surrounded by a rcm. Yet other devices are mechanical in nature, and include active compound-filled electrical or osmotic pumps.
  • the subdermally implantable devices of the present invention can be prepared in a variety of sizes and shapes to accommodate such factors as the specific implantation site and the desired release rate of the drug.
  • the device is substantially cylindrical in shape having a preferred overall length of from about 4.2 cm to about 4.6 cm, and a preferred overall diameter of from about 2.3 mm to about 2.7 mm.
  • the central core is rod-shaped, and has a preferred length of from about 3.8 cm to about 4.2 cm, and a preferred diameter of from about 2.0 mm to about 2.2 mm.
  • the length of the implantable device can be varied to deliver different amounts of the drug.
  • the subdermally implantable devices according to the present invention can be easily fabricated in accordance with standard techniques.
  • the desired shape of the resultant dispersion is achieved by molding, casting extrusion, or other appropriate process.
  • the matrix material contains polymers such as silicone elastomers, an additional curing step may be necessary.
  • the intermediate layer is then applied to the thus-shaped matrix, e.g., by swelling, coating or laminating according to known techniques, a polymeric tube in water and then placing it over the matrix and allowing the polymer to dry in place, or by mechanical lapping.
  • the outer layer can likewise be applied in a variety of ways such as by mechanical stretching, swelling or dipping. See, for example, U.S. Pat. Nos. 3,832,252, 3,854,480 and 4,957,119.
  • U.S. Patent No. 5,756,115 describes a loading and using a subdermal delivery system for delivering contraceptives.
  • the dimensions of the implant are also determined on the basis of the implantation method.
  • the devices of the present invention can be implanted into a subject in accordance with standard procedures.
  • the present invention provides subdermal drug delivery devices containing mifepristone, Compositions D1-D5 or other GRII antagonists (Drugs).
  • the drug is present in the implantable devices in a therapeutically effective amount, i.e., an amount effective to allow the device to deliver sufficient amount of the drug to achieve a desired therapeutic result in the treatment of a condition.
  • controlled-release dosage forms include the pharmacokinetic ability to maintain a preplanned blood level of an administered drug over a comparatively longer period of time.
  • the therapeutic benefits include also a simultaneous increase in patient compliance and a reduction in the number of doses of drug administered to a patient.
  • Additional semipermeable polymers comprise acetaldehyde dimethylcellulose acetate; cellulose acetate ethylcarbamate; cellulose acetate methylcarbamate; cellulose diacetate propylcarbamate; cellulose acetate diethylaminoacetate; ethyl acrylate methyl methacrylate, semipermeable polyamide; semipermeable polyurethane; semipermeable sulfonated polystyrene; semipermeable crosslinked selective polymer formed by the coprecipation of a polyanion and polycation, as disclosed in U.S. Pat. Nos.
  • the polymers are known to the polymer art in U.S. Pat. Nos. 3,845,770; 3,916,899 and 4,160,020; and in Handbook of Common Polymers, by Scott, J. R. and Roff, W. J. 1971, CRC Press, Cleveland, Ohio.
  • Wall 12, in a present manufacture can be coated from a substantially single solvent system, such as acetone if coated from a solution, or water if coated as a dispersion.
  • the present invention provides delivery of mifepristone, Compositions D1-D5 or other GRII antagonists (Drugs) via a sustained release or controlled release delivery techniques.
  • Herpes simplex virus trans-regulatory protein ICP27 stabilizes and binds to 3' ends of labile niRNA, J. Virol. 69 (1995), pp. 7187-7195.
  • Smiley, Herpes simplex virus ICP27 induces cytoplasmic accumulation of unspliced polyadenylated alpha-globin pre-mRNA in infected HeLa cells, J. Virol. 74 (2000), pp. 2913-2919.
  • Pestivirus internal ribosome entry site IRES
  • Gallie 2002 D.R. Gallie, Protein-protein interactions required during translation, Plant MoI. Biol. 50 (2002), pp. 949-970.
  • Kieft JS Zhou K, Jubin R, Murray MG, Lau JY, Doudna JA. 1999.
  • the hepatitis C virus internal ribosome entry site adopts an ion-dependent tertiary fold.
  • Kieft JS Zhou K, Jubin R, Doudna JA. 2001. Mechanism of ribosome recruitment by hepatitis C virus IRES. RNA. 7:194-206.
  • RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 59 noncoding region. RNAl:526-537.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques contenant des antagonistes du récepteur glucocorticoïde de type II, leurs énantiomères et isomères, composés antisens, ARN inhibiteur, et composés mimétiques peptidiques, ciblés sur EIF3/mov34 et/ou GR I, servant à traiter les infections par les virus Herpès Simplex (types I et II). L'invention concerne également des méthodes permettant de traiter des individus présentant une infection par un virus Herpes Simplex (types 1 and 2).
PCT/US2006/021931 2005-06-06 2006-06-06 Medicaments anti-vhs WO2006133198A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68783905P 2005-06-06 2005-06-06
US60/687,839 2005-06-06

Publications (2)

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WO2006133198A2 true WO2006133198A2 (fr) 2006-12-14
WO2006133198A3 WO2006133198A3 (fr) 2007-05-31

Family

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3400233A4 (fr) * 2015-08-03 2020-02-26 Pop Test Oncology LLC Compositions pharmaceutiques et méthodes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2529852A1 (fr) * 2003-06-20 2004-12-29 Viral Genomix, Inc. Compositions et procedes de traitement du vih

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3400233A4 (fr) * 2015-08-03 2020-02-26 Pop Test Oncology LLC Compositions pharmaceutiques et méthodes

Also Published As

Publication number Publication date
WO2006133198A3 (fr) 2007-05-31

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